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PubMed2002

Association of a polymorphism in the P2X7 gene with tuberculosis in a Gambian population.

Adenosine triphosphate (ATP) ligation of P2X(7) receptors expressed on human macrophages that are infected with mycobacteria induces cell death and subsequent loss of intracellular bacterial viability. Marked heterogeneity observed in cell donor ATP responsiveness suggests that this antimycobacterial mechanism may be genetically regulated. Five single-nucleotide polymorphisms (SNPs) previously identified in a putative 1.8-kb promoter region upstream of P2RX7 exon 1 were screened for associations with clinical tuberculosis. The frequencies of these promoter SNPs and a polymorphism in P2RX7 exon 13 at position 1513 were compared among >300 Gambian patients with tuberculosis and >160 ethnically matched control subjects by sequence-specific oligonucleotide hybridization and ligation detection reaction analysis. A significant protective association against tuberculosis was found for 1 promoter SNP, at nucleotide position -762 (odds ratio [OR] for variant C allele, 0.70; 95% confidence interval [CI], 0.54-0.89; P=.003; OR for CC genotype, 0.545; 95% CI, 0.318-0.934; P=.027). This association supports a role for ATP/P2X(7)-mediated host regulation of Mycobacterium tuberculosis infection.

Adult↗
PubMed2004

Towards optimally multiplexed applications of universal arrays.

We study a design and optimization problem that occurs, for example, when single nucleotide polymorphisms (SNPs) are to be genotyped using a universal DNA tag array. The problem of optimizing the universal array to avoid disruptive cross-hybridization between universal components of the system was addressed in previous work. Cross-hybridization can, however, also occur assay specifically, due to unwanted complementarity involving assay-specific components. Here we examine the problem of identifying the most economic experimental configuration of the assay-specific components that avoids cross-hybridization. Our formalization translates this problem into the problem of covering the vertices of one side of a bipartite graph by a minimum number of balanced subgraphs of maximum degree 1. We show that the general problem is NP-complete. However, in the real biological setting, the vertices that need to be covered have degrees bounded by d. We exploit this restriction and develop an O(d)-approximation algorithm for the problem. We also give an O(d)-approximation for a variant of the problem in which the covering subgraphs are required to be vertex disjoint. In addition, we propose a stochastic model for the input data and use it to prove a lower bound on the cover size. We complement our theoretical analysis by implementing two heuristic approaches and testing their performance on synthetic data as well as on simulated SNP data.

Algorithms↗
PubMed2006

The role of polymorphisms in ADAM33, a disintegrin and metalloprotease 33, in childhood asthma and lung function in two German populations.

BACKGROUND: ADAM33, the first asthma candidate gene identified by positional cloning, may be associated with childhood asthma, lung function decline and bronchial hyperresponsiveness. However, replication results have been inconclusive in smaller previous study populations probably due to inconsistencies in asthma phenotypes or yet unknown environmental influences. Thus, we tried to further elucidate the role of ADAM33 polymorphisms (SNPs) in a genetic analysis of German case control and longitudinal populations. METHODS: Using MALDI-TOF, ten ADAM33 SNPs were genotyped in 1,872 children from the International Study of Asthma and Allergy in Childhood (ISAAC II) in a case control setting and further 824 children from the longitudinal cohort Multicentre Study of Allergy (MAS). In both populations the effects of single SNPs and haplotypes were studied and a gene environment analysis with passive smoke exposure was performed using SAS/Genetics. RESULTS: No single SNP showed a significant association with doctor's diagnosis of asthma. A trend for somewhat more profound effects of ADAM33 SNPs was observed in individuals with asthma and BHR. Haplotype analyses suggested a minor effect of the ADAM33 haplotype H4 on asthma (p = 0.033) but not on BHR. Associations with non atopic asthma and baseline lung function were identified but no interaction with passive smoke exposure could be detected. CONCLUSION: The originally reported association between ADAM33 polymorphisms and asthma and BHR could not be confirmed. However, our data may suggest a complex role of ADAM33 polymorphisms in asthma ethiology, especially in non atopic asthma.

ADAM Proteins↗
PubMed2002

Association analysis of single nucleotide polymorphisms in cartilage-specific collagen genes with knee and hip osteoarthritis in the Japanese population.

Osteoarthritis (OA) is one of the most common diseases in the elderly. Although its pathophysiology is complex and its molecular basis remains to be determined, much evidence suggests that OA has strong genetic determinants. To search for susceptibility loci of OA, we selected seven candidate genes encoding cartilage-specific collagens (type II, IX, X, and XI collagens) and performed association analysis for OA using single nucleotide polymorphisms (SNPs) in the coding region of these genes. Four hundred seventeen OA samples and 280 control samples were collected from the Japanese population, and 12 SNPs were genotyped. Our studies have identified two susceptibility loci of OA: COL2A1 and COL9A3. An SNP in COL9A3 showed significant association with knee OA (p = 0.002, odds ratio [OR] = 1.48). Haplotype analysis showed significant association between a specific haplotype of COL2A1 and hip OA (p = 0.024; OR = 1.30). Further analysis of these two genes will shed light on the molecular mechanisms of OA.

Aged↗
PubMed2006

A polymorphism in the 5'-untranslated region of the porcine cholecystokinin type a receptor gene affects feed intake and growth.

The location and utilization of quantitative trait loci (QTL) and candidate genes with significant effects on economically important traits are becoming increasingly important in livestock breeding programs. The porcine cholecystokinin type A receptor (CCKAR) is a candidate gene for performance traits, due to its known role in the physiological control of feed intake, satiety, and obesity. We investigated the association of CCKAR polymorphisms with feeding, growth, and efficiency traits in an F2 population derived from a cross between Meishan and Large White founder animals and in lines of Large White pigs that had been divergently selected on the basis of lean growth efficiency traits. In the F2 population, CCKAR genotype was significantly associated with daily feed intake and average daily gain. The effects of the polymorphisms were then assessed in a larger-scale analysis of segregating commercial lines. A newly discovered single-nucleotide polymorphism (SNP) within the 5'-untranslated region (5'-UTR) had highly significant effects on feed intake, average daily gain, and days to 110 kg, which were not seen for a previously reported SNP within the CCKAR gene. Furthermore, we provide evidence that the novel SNP disrupts the binding of the YY1 transcription factor, which raises the possibility that it is the causal variant. The 5'-UTR SNP could be utilized as a molecular genetic test for increased feed intake, faster lean growth, and reduced days to market weight in segregating commercial lines.

5' Untranslated Regions↗
PubMed2005

Analysis of the genetic diversity of the Plasmodium falciparum multidrug resistance gene 5' upstream region.

Recent findings indicating a low level of polymorphism in the Plasmodium falciparum genome have led to the hypothesis that existent polymorphisms are likely to have functional significance. We tested this hypothesis by developing a map of the polymorphism in the P. falciparum multidrug resistance 1 (pfmdr1) gene 5' upstream region and assaying its correlation with drug resistance in a sample of field isolates from Dakar, Senegal. A comparison of six geographically diverse laboratory strains showed that the 1.94-kb 5'-untranslated region is highly monomorphic, with a total of four unique single nucleotide polymorphisms (SNPs) being identified. All of the mutations were localized to a 462-basepair region proximal to the transcription start point. Analysis of this region in field isolates shows the prevalence of one SNP throughout the entire population of parasites, irrespective of drug resistance status. The SNP frequency of the pfmdr1 upstream region is lower than that found in the noncoding region of other genes.

ATP-Binding Cassette Transporters↗
PubMed2001

High-throughput genomic and proteomic analysis using microarray technology.

BACKGROUND: High-density microarrays are ideally suited for analyzing thousands of genes against a small number of samples. The next step in the discovery process is to take the resulting genes of interest and rapidly screen them against thousands of patient samples, tissues, or cell lines to further investigate their involvement in disease risk or the response to medication. METHODS: We used a microarray technology platform for both single-nucleotide polymorphisms (SNPs) and protein expression. Each microarray contains up to 250 elements that can be customized for each application. Slides contained either a 16- or 96-microarray format (4000-24,000 elements per slide), allowing the corresponding number of samples to be rapidly processed in parallel. RESULTS: Results for SNP genotyping and protein profiling agreed with results of restriction fragment length polymorphism (RFLP) analysis or ELISA, respectively. Genotyping analyses, using the microarray technology, on large sample sets over multiple polymorphisms in the NAT2 gene were in full agreement with traditional methodologies, such as sequencing and RFLP analysis. The multiplexed protein microarray had correlation coefficients of 0.82-0.99 (depending on analyte) compared with ELISAs. CONCLUSIONS: The integrated microarray technology platform is adaptable and versatile, while offering the high-throughput capabilities needed for drug development and discovery applications.

Arylamine N-Acetyltransferase↗
PubMed2004

The allele frequency spectrum in genome-wide human variation data reveals signals of differential demographic history in three large world populations.

We have studied a genome-wide set of single-nucleotide polymorphism (SNP) allele frequency measures for African-American, East Asian, and European-American samples. For this analysis we derived a simple, closed mathematical formulation for the spectrum of expected allele frequencies when the sampled populations have experienced nonstationary demographic histories. The direct calculation generates the spectrum orders of magnitude faster than coalescent simulations do and allows us to generate spectra for a large number of alternative histories on a multidimensional parameter grid. Model-fitting experiments using this grid reveal significant population-specific differences among the demographic histories that best describe the observed allele frequency spectra. European and Asian spectra show a bottleneck-shaped history: a reduction of effective population size in the past followed by a recent phase of size recovery. In contrast, the African-American spectrum shows a history of moderate but uninterrupted population expansion. These differences are expected to have profound consequences for the design of medical association studies. The analytical methods developed for this study, i.e., a closed mathematical formulation for the allele frequency spectrum, correcting the ascertainment bias introduced by shallow SNP sampling, and dealing with variable sample sizes provide a general framework for the analysis of public variation data.

Black or African American↗
PubMed2006

Glutamine protects articular chondrocytes from heat stress and NO-induced apoptosis with HSP70 expression.

OBJECTIVE: To investigate the effect of l-glutamine (Gln) on stress responses of chondrocytes exposed to heat stress or nitric oxide (NO). METHODS: Cultures of articular chondrocytes were established from rabbit joints, and treated for 12h with various concentrations of Gln (0-20 mM). In some experiments, cells were also treated with quercetin (Que), a heat shock protein 70 (HSP70) inhibitor. Heat stress (43 degrees C) was applied to the cells for 0-120 min. Apoptosis was induced by 0.5mM sodium nitroprusside (SNP) dihydrate that produces NO. After stress loading, HSP70 expression was detected by Western blot analysis. Cell viability was assessed by lactate dehydrogenase (LDH) release and tetrazolium salt-based assays, while apoptosis was evaluated by Hoechst 33342 staining, TUNEL methods and active caspase-3 determination. RESULTS: Gln demonstrated dose-dependent enhancing effect on stress-mediated induction of HSP70, while in the absence of any stress HSP70 was not induced by Gln alone. After heating or SNP loading, chondrocytes showed severe reduction in viability, while the cytotoxic outcome was almost completely abrogated by conditioning with Gln. The protective effect of Gln was significantly blocked by Que that effectively suppressed stress-induced HSP70 expression in chondrocytes. The Gln also rendered chondrocytes unsusceptible to NO-induced apoptosis that was frequently seen in SNP-treated culture. CONCLUSION: This study demonstrated that the treatment of chondrocytes with Gln protected the cells from heat stress and NO-induced apoptosis. These chondroprotective effects of Gln may be mediated by HSP70.

Animals↗
PubMed2006

Polymorphisms in genes involved in GH1 release and their association with breast cancer risk.

The regulation of growth hormone 1 (GH1) and insulin-like-growth factor-1 (IGF-1) release is under the influence of three pituitary hormones [growth hormone releasing hormone (GHRH), ghrelin (GHRL) and somatostatin (SST)], which act in an autocrine/paracrine fashion in the breast. By binding to their respective receptors, they control cell proliferation, differentiation and apoptosis in a GH1/IGF-1-dependent manner. We investigated single nucleotide polymorphisms (SNPs) in the GHRH, GHRHR, GHRL, GHSR, SST and SSTR2 gene regions in a Polish and a German cohort of 798 breast cancer cases and 1011 controls. Our study revealed an association of a novel TC repeat polymorphism in the SST promoter with a decreased breast cancer risk in the Polish study population [odds ratio (OR), 0.65; 95% confidence interval (CI), 0.44-0.96]. The closely linked SNP IVS1 A+46G showed the same trend. For both polymorphisms the association was stronger in women above the age of 50 (OR, 0.33; 95% CI, 0.14-0.76 and OR, 0.39; 95% CI, 0.18-0.87, respectively). The protective effect of these polymorphisms was confirmed in a haplotype analysis among women above 50 years of age and carrying the two variant alleles (OR, 0.37; 95% CI, 0.17-0.80). In the independent German population, we observed slightly decreased ORs among women above the age of 50 years. In the SSTR2 gene, carriers of the promoter 21/21 TG repeat genotype were at a decreased breast cancer risk (OR, 0.62; 95% CI, 0.41-0.94) compared to carriers of the other genotypes in the Polish population. Furthermore, we identified a protective effect of the GHRHR C-261T SNP in both populations (joint analysis CT+TT versus CC: OR, 0.80; 95% CI, 0.65-0.99). This effect was carried by a haplotype containing the protective allele. Thus, our study concludes a possible protective influence of distinct polymorphisms in genes involved in GH1 release on breast cancer risk.

Adolescent↗
PubMed2005

An analysis of identical single-nucleotide polymorphisms genotyped by two different platforms.

The overlap of 94 single-nucleotide polymorphisms (SNP) among the 4,720 and 11,120 SNPs contained in the linkage panels of Illumina and Affymetrix, respectively, allows an assessment of the discrepancy rate produced by these two platforms. Although the no-call rate for the Affymetrix platform is approximately 8.6 times greater than for the Illumina platform, when both platforms make a genotypic call, the agreement is an impressive 99.85%. To determine if disputed genotypes can be resolved without sequencing, we studied recombination in the region of the discrepancy for the most discrepant SNP rs958883 (typed by Illumina) and tsc02060848 (typed by Affymetrix). We find that the number of inferred recombinants is substantially higher for the Affymetrix genotypes compared to the Illumina genotypes. We illustrate this with pedigree 10043, in which 3 of 7 versus 0 of 7 offspring must be double recombinants using the genotypes from the Affymetrix and the Illumina platforms, respectively. Of the 36 SNPs with one or more discrepancies, we identified a subset that appears to cluster in families. Some of this clustering may be due to the presence of a second segregating SNP that obliterates a XbaI site (the restriction enzyme used in the Affymetrix platform), resulting in a fragment too long (>1,000 bp) to be amplified.

Female↗
PubMed1999

Phenotypic changes in rat and guinea pig coronary microvascular endothelium after culture: loss of nitric oxide synthase activity.

OBJECTIVES: Coronary microvascular endothelial cells (CMVEs) can modulate the contractile performance of the adjacent myocardium by the release of agents such as nitric oxide (NO). Most previous studies using CMVEs have been done in situ, in the intact organ. We set out to study possible differences in NO synthase (NOS) regulation between freshly isolated and cultured rat and guinea pig CMVEs. METHODS: CMVEs were isolated from Wistar rats and Dunkin Hartley guinea pigs and then grown in culture for varying times. Fura-2 fluorescence was used to measure agonist-induced changes in CMVE intracellular calcium levels. Agonist-induced changes in CMVE cGMP levels were measured by commercial radioimmunoassay kit. Western blot analysis was used to measure endothelial, constitutive NOS (ecNOS) and soluble guanylate cyclase (sGC) protein levels. Reverse transcription, polymerase chain reactions and Southern blotting were used to measure ecNOS mRNA transcripts. RESULTS: In both fresh (1 h post-isolation) and cultured (14 days with one passage) CMVEs of the rat and guinea pig, bradykinin (BK) and the calcium ionophore A23187 (both 1 microM) elicited significant (P < 0.01) increases in the fura-2 340/380 fluorescence ratio. In cultured CMVEs, basal cGMP levels were unaffected by exposure to BK or A23187. Exposure to sodium nitroprusside (SNP) or atrial natriuretic peptide (ANP) (both 1 microM) induced significant (P < 0.01) increases in cGMP in guinea pig cells, whereas in rat cells only ANP produced a significant (P < 0.01) response. By contrast, freshly isolated CMVEs of both species had higher basal cGMP levels than cultured cells, and on exposure to BK and A23187, responded with significant (P < 0.01) increases in cGMP. Moreover, exposure of both fresh rat and guinea pig CMVEs to SNP or ANP also resulted in significant (P < 0.01) increases in cGMP. Western blot analysis demonstrated that ecNOS and sGC protein were lost from the rat CMVEs following culture. Furthermore, there was also a significant loss of ecNOS mRNA from the rat cells following culture. CONCLUSIONS: These data demonstrate that freshly isolated rat and guinea pig CMVEs possess ecNOS activity, and that this activity is downregulated following culture. At least for the rat, this effect would seem to lie at both the transcriptional and translational level. Furthermore, rat CMVEs have reduced activity of sGC following culture.

Analysis of Variance↗
PubMed2004

Variation in the lamin A/C gene: associations with metabolic syndrome.

OBJECTIVE: Metabolic syndrome is associated with increased risk for cardiovascular disease and type 2 diabetes mellitus (T2DM). The lamin A/C (LMNA) gene, mutations of which cause rare syndromes of severe insulin resistance and dyslipidemia, is located on chromosome 1q21-q24, a region linked to T2DM in several genome wide scans, including in the Old Order Amish. To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components. METHODS AND RESULTS: We performed DNA sequence analysis of LMNA. Six single-nucleotide polymorphisms (SNPs) were identified: c.141889C>T (intron 3), c.141906G>T (intron 3), A287A (c.141253T>C; exon 5), c.140353G>A (intron 6), c.139418C>T (intron 8), and H566H (c. 138747C>T; exon 10). In 971 participants from the Amish Family Diabetes Study, the H566H polymorphism of LMNA was associated with metabolic syndrome diagnosed according to National Cholesterol Education Program ATP III criteria and also higher mean fasting triglyceride and lower mean high-density lipoprotein-cholesterol concentrations. However, no differences in allele frequencies were observed for any SNP among participants with T2DM or impaired glucose homeostasis (IGH) and normoglycemic controls. Haplotype analysis showed that >87% of individuals carried 1 of 2 common LMNA haplotypes. There were no significant differences in haplotype frequencies among subjects with metabolic syndrome T2DM, IGH, and controls. CONCLUSIONS: Sequence variation in LMNA may confer modest susceptibility for development of metabolic syndrome and dyslipidemia in the Amish. To determine whether polymorphisms in LMNA influence susceptibility to metabolic syndrome and its constituent components, we performed DNA analysis of polymorphisms in LMNA. The H566H polymorphism was associated with metabolic syndrome and also higher mean fasting triglyceride and lower mean HDL-cholesterol concentrations in the Old Order Amish.

Adult↗
PubMed2002

Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools.

Detecting alleles that confer small increments in susceptibility to disease will require large-scale allelic association studies of single-nucleotide polymorphisms (SNPs) in candidate, or positional candidate, genes. However, current genotyping technologies are one to two orders of magnitude too expensive to permit the analysis of thousands of SNPs in large samples. We have developed and thoroughly validated a highly accurate protocol for SNP allele frequency estimation in DNA pools based upon the SNaPshot (Applied Biosystems) chemistry adaptation of primer extension. Using this assay, we were able to estimate the difference in allele frequencies between pooled cases and controls (Delta) with a mean error of 0.01. Moreover, when we genotyped seven different SNPs in a single multiplex reaction, the results were similar, with a mean error for Delta of 0.008. The assay performed well for alleles of low frequency alleles (f approximately 0.05) and was accurate even with relatively poor quality DNA template extracted from mouthwashes. Our assay conditions are generalisable, universal, robust and, therefore, for the first time, permit high-throughput association analysis at a realistic cost.

DNA↗
PubMed2002

Reduced DAT- and DBH-immunostaining in the limbic system of Sardinian alcohol-preferring rats.

We have recently shown that tyrosine-hydroxylase immunostaining (TH-IM) is selectively decreased in the cingulate cortex and in the shell of the nucleus accumbens (nAcc) of Sardinian alcohol-preferring rats (sP) when compared with Sardinian alcohol-non preferring (sNP) and Wistar (W) rats. Since these regions contain both dopamine and noradrenaline (NA) fibers, clarification of the dopaminergic and noradrenergic contribution to the decreased TH-immunoreactivity was needed. To this aim, we carried out the present immunohistochemistry study using two antibodies raised against dopamine beta-hydroxylase (DBH), the enzyme responsible for the conversion of dopamine into noradrenaline, and against the dopamine transporter (DAT), as markers for noradrenergic and dopaminergic fibers, respectively. The results show that DBH-immunostaining (DBH-IM) and DAT-immunostaining (DAT-IM) were both lower in the cingulate cortex of the sP rats with respect to sNP and W rats. In the shell of the nAcc a reduced DAT-IM in sP rats was found, while the DBH-IM did not differ between the three lines of rats. The analysis of the cell-body area of noradrenergic neurons in the locus coeruleus, revealed no differences between sP, sNP and W rats. These results indicate a selective reduction of the terminal innervation in the mesocorticolimbic dopamine and NA systems in sP rats. This genetically-determined difference may be involved in the opposite alcohol preference and consumption of sP and sNP rats.

Alcohol Drinking↗
PubMed2000

Molecular evolution and intratumor heterogeneity by topographic compartments in muscle-invasive transitional cell carcinoma of the urinary bladder.

Superficial transitional cell carcinomas (TCC) of the urinary bladder have been shown to be monoclonal. However, no combined study of clonality and tumor suppressor genes (TSG) is available to date for muscle-invasive TCC. Forty-four muscle-invasive TCC of the urinary bladder selected from women were included in this study. Tumor cells located above and below the muscularis mucosa zone were systematically microdissected and used for DNA extraction. Hha-I digested and undigested samples were used to study the methylation pattern of androgen receptor alleles and undigested samples were used for microsatellite analysis of TSG (TP53, RB1, WT1, and NF1). Both loss of heterozygosity (LOH) and single nucleotide polymorphism (SNP) analyses were performed using optimized denaturing gradient gel electrophoresis. The expression of p53, pRB, and p21WAF1 was assessed by immunohistochemistry. Appropriate controls were run in every case. All except two TCC showed a monoclonal pattern with the same allele inactivated in both compartments. Microsatellite analysis of TSG revealed the same LOH/SNP pattern in both tumor compartments in 30 cases (involving more than 1 TSG locus in 8) and genetic heterogeneity in 14 cases. From the latter group, 9 cases expressed more genetic changes in the deep compartment (involving TP53 gene in all cases, WT1 gene in 2, and NF1 in 1), whereas in 4 cases the superficial compartment showed more genetic changes (three involving NF1 and one involving both RB and TP53). No statistical difference in the immunoexpression was detected, although it tended to be higher in the superficial compartment than in the deep compartment. These concordant data in polymorphic DNA regions indicate that bladder-muscle-invasive TCC are monoclonal proliferations with homogeneous tumor cell selection. Heterogeneous tumor cell selection by topography defined two different genetic compartments: superficial, NF1-defective, and deep, TP53-defective. No differences in the immunohistochemical expression were observed, precluding a more extensive clinical application.

Base Sequence↗
PubMed2026

Microsatellites Versus Genome-Wide SNPs Data for Pedigree Reconstruction in Twin Simmental Crossbred Cattle.

Accurate pedigree reconstruction is critical for genetic evaluation in admixed cattle populations, yet the relative performance of microsatellite and genome-wide SNP markers in twin-rich herds with incomplete pedigree records remains unclear. We compared 12 ISAG-recommended microsatellite markers with whole-genome SNP data for dam-calf assignment in a Simmental crossbred population (n = 43, 13 dam-calf groups) from southern China. Twin zygosity was determined from SNP identity-by-descent (PI_HAT) values: nine calf pairs were dizygotic, one pair was monozygotic (20A/21A), and one adult pair was composed of dizygotic twin sisters (31A/34A). Admixture analysis at K = 3 revealed ancestry proportions of 50.7% European taurine, 28.9% Chinese indicine and 20.4% East Asian taurine. The SNP-based neighbor-joining tree correctly recovered 12 of 13 groups (92.3%, 95% CI: 64.0-99.8%), whereas the microsatellite-based tree recovered 11 (84.6%, 95% CI: 54.6-98.1%); the difference was not statistically significant (exact McNemar test, p = 1.0). Locus INRA023 was monomorphic (PIC = 0), reducing the effective number of markers to 11. These results indicate that genome-wide SNPs show a favourable trend in accuracy and are less prone to false-positive clustering than a standard microsatellite panel in admixed, twin-rich cattle populations.

SNP↗
PubMed2006

Eotaxin polymorphisms and serum total IgE levels in children with asthma.

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. OBJECTIVE: To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. METHODS: Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. RESULTS: One SNP, -384A>G, was associated with asthma among African American families (P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, -426C and IVS2+199A, were associated with lower serum total IgE levels (P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, -576C and g.4438C, were associated with higher IgE levels in African American families (P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV(1), or airway responsiveness. CONCLUSION: These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma.

Adult↗